Clinical study of ruxolitinib and venetoclax for children with relapsed or refractory leukemia or lymphoma with mutations in the IL-7R/JAK-STAT signalling pathway - HEM-iSMART Sub-protocol C

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Princess Maxima Center For Pediatric Oncology

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Trial duration

8 Sep 2025 → ongoing

Decision date (initial)

2024-11-08

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Fight Kids Cancer - funding · Abbvie - IMP Venetoclax (including labeling) + monetary support for drug distribution · Novartis - IMP Ruxolitinib

External identifiers

EU CT number

2022-501867-42-01

ClinicalTrials.gov

NCT05745714

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Phase I: To assess the safety and tolerability of the investigational agents and define the MTD/RP2D(s);
Phase II: To evaluate the activity of new drugs in T-ALL/T-LBL patients harboring specific alterations linked to mechanism of action of these drugs

Conditions and MedDRA coding

Acute Lymphoblastic Leukemia, in Relapse Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Recurrent Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Recurrent Lymphoblastic Lymphoma (Precursor B-Lymphoblastic Lymphoma/Leukaemia) Refractory Lymphoblastic Lymphoma (Precursor T-Lymphoblastic Lymphoma/Leukaemia) Refractory

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Children between 1 year (≥ 12 months) and 18 years of age at the time of first diagnosis and less than 21 years at the time of inclusion and able to swallow tablets.
2. Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥ 50%
3. Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study specific screening procedures are conducted, according to local, regional or national guidelines.
4. Patients must have had advanced molecular profiling and flow-cytometric analysis of their recurrent or refractory disease at a time-point before the first inclusion into this trial (see section 9.1 for detailed description of the molecular diagnostics required). Drug response profiling and methylation is highly recommended but not mandatory. Patients with molecular profiling at first diagnosis lacking molecular diagnostics at relapse or refractory disease may be allowed to be included after discussion with the sponsor.
5. Patients whose tumor presents alterations in the IL-7R and/or JAK-STAT signaling pathways including but not limited to the following are eligible: CRLF2: Rearrangements and mutations leading to CRLF2 overexpression (P2RY8-CRLF2, IGH-CRLF2, and CRLF2 F232C), CRFL2 overexpression; EPOR: Truncating rearrangements or mutations in exon 8, EPOR fusions; JAK1/2/3: Recurrent or novel missense and in-frame indel mutations in or flanking the pseudokinase and kinase domains, JAK fusion; IL-7R: Recurrent or novel missense or in-frame indel mutations in the transmembrane domain; SH2B3: Copy number deletions, or mutations that result in frameshifts or premature termination; JAK2: In frame fusions retaining the tyrosine kinase domain; USP9X truncating mutation or USP9X-DDX3X fusion; STAT5B and DNM2 mutations; PTPN2 deletion described as involved in IL7R/JAK/STAT pathway activation; IL7R mutations
6. Adequate organ function: -RENAL AND HEPATIC FUNCTION (Assessed within 48 hours prior to C1D1): o Serum creatinine ≤ 1.5 x upper limit of normal (ULN) for age or calculated creatinine clearance as per the Schwartz formula or radioisotope glomerular filtration rate ≥ 60 mL/min/1.73 m2. o Direct bilirubin ≤ 2 x ULN (≤ 3.0 × ULN for patients with Gilbert’s syndrome). o Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT ≤ 5 x ULN. Note: Patients with hepatic dysfunction related to the underling disease can be eligible even if they do not fulfill the aforementioned values for hepatic transaminases. In these cases, patients need to be discussed with the sponsor to confirm the eligibility. -CARDIAC FUNCTION: o Shortening fraction (SF) >29% (>35% for children < 3 years) and/or left ventricular ejection fraction (LVEF) ≥50% at baseline, as determined by echocardiography or MUGA. o Absence of QTcF prolongation (QTc prolongation is defined as >450 msec on baseline ECG, using the Friedericia correction), or other clinically significant ventricular or atrial arrhythmia.

Exclusion criteria 21

1. Pregnancy or positive pregnancy test (urine or serum) in females of childbearing potential. Pregnancy test must be performed within 7 days prior to C1D1.
2. Sexually active participants not willing to use highly effective contraceptive method (pearl index <1) as defined in CTFG HMA 2020 (Appendix II) during trial participation and until 6 months after end of anti-leukemic therapy.
3. Breast feeding
4. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome) in case of oral IMPs.
5. Patients whose tumor present known mutations conferring resistance to JAK inhibitors: JAK1 Phe958 and Pro960 mutations and JAK2 Y931C mutations.
6. Patients whose tumor present known mutations conferring resistance to venetoclax (e.g. BCL2 mutations of venetoclax binding-site (Gly101Val mutation, Phe104Leu/Cys mutations).
7. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to the study drugs, or drugs chemically related to study treatment or excipients that contraindicate their participation, including conventional chemotherapeutics (i.e. cytarabine and cyclophosphamide when applicable, intrathecal agents) and corticoids.
8. Known active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
9. Severe concomitant disease that does not allow treatment according to the protocol at the investigator’s discretion.
10. Subjects unwilling or unable to comply with the study procedures.
11. Previous treatment with ruxolitinib and venetoclax in combination (Patients who have previously received any of these two drugs separately can be eligible for this sub-protocol).
12. Current use of a prohibited medication or herbal preparation or requires any of these medications during the study. See Section 7, Appendix III and IV for details. In general, CYP3A4 inhibitors/Pgp inhibitors, moderate or strong inducers of CYP3A4 or drugs inducing QTc changes (prolongation of the QT interval or inducing Torsade de Points) are not permitted. Among others and not exclusively that relates to antiviral, antifungal, antibiotic, antimalarial, antipsychotic and anti-depressive drugs.
13. Patients who have consumed grapefruit, grapefruit products, Seville oranges (Including marmalade containing Seville oranges) or starfruit within 72 hours prior to the first dose of study drug.
14. Unresolved toxicity greater than NCI CTCAE v 5.0 ≥ grade 2 from previous anti-cancer therapy, including major surgery, except those that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profile of the study treatment (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based chemotherapy) (Common Terminology Criteria for Adverse Events (CTCAE) (cancer.gov).
15. Active acute graft versus host disease (GvHD) of any grade or chronic GvHD of grade 2 or higher. Patients receiving any agent to treat or prevent GvHD post bone marrow transplant are not eligible for this trial.
16. Received immunosuppression post allogenic HSCT within one month of study entry.
17. History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying diagnosis.
18. History of progressive multifocal leuko-encephalopathy (PML).
19. History of endocrine or kidney related growth retardation prior to the underlying diagnosis.
20. Evidence of clinically active tuberculosis (clinical diagnosis per local practice).
21. Wash-out periods of prior medication: a. CHEMOTHERAPY: At least 7 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea, 6-mercaptopurine, oral methotrexate and steroids which are permitted up until 48 hours prior to initiating protocol therapy. Patients may have received intrathecal therapy (IT) at any time prior to study entry. b. RADIOTHERAPY: Radiotherapy (non-palliative) within 21 days prior to the first dose of drug. Palliative radiation in past 21 days is allowed. c. HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT): a. Autologous HSCT within 2 months prior to the first study drug dose. b. Allogeneic HSCT within 3 months prior to the first study drug dose. d. IMMUNOTHERAPY: At least 42 days must have elapsed after the completion of any type of immunotherapy other than monoclonal antibodies (e.g. inotuzumab). e. MONOCLONAL ANTIBODIES AND INVESTIGATIONAL DRUGS: At least 21 days or 5 times the half-life (whichever is shorter) from prior treatment with monoclonal antibodies or any investigational drug under investigation must have elapsed before the first study drug. f. SURGERY: Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I: determine the maximum tolerated dose (MTD)
2. Phase II: Best Overall Response Rate (ORR)

Secondary endpoints 8

1. Overall survival (OS) is defined as time from C1D1 until death of any cause. Patients still alive at the time of clinical cut-off date will be censored at their last known date alive.
2. Event-free survival (EFS) is defined as time from C1D1 to the first event (subsequent relapse after CR (including molecular reappearance), death of any cause, failure to achieve remission (CR, CRp or CRi), or secondary malignancy). Patients who are event-free will be censored at date of last adequate disease assessment. Treatment failure (defined by morphology and/or flow-cytometry as not achieving remission after 1 cycle) is calculated as an event at day 1.
3. Cumulative incidence of relapse (CIR): Estimate of the risk, that a patient will develop a relapse over a specified period of time. Deaths without relapse will be considered competing events.
4. Number of patients proceeding to HSCT after the experimental therapy: The rate of those proceeding to subsequent allogenic hematopoietic stem cell transplantation as consolidation therapy is calculated as the number of patients who receive an HSCT divided by the total number of patients enrolled.
5. Cumulative overall response rate (ORR), defined as the CR, CRp, CRi and MRD neg-ativity rates after more than 1 cycle of treatment. The best overall response is the best response recorded from the start of the treatment until patient gets off-study or the cut-off date, whichever comes first (taking as reference for progressive disease the small-est measurements recorded since the treatment started).
6. Rate of dose limiting toxicities (DLTs); number of participants with dose limiting toxicities.
7. PK parameters, including but not limited to plasma concentration time profiles, AUClast, AUCtau, Cmin, Cmax, Tmax, clearance, half-life time.
8. QoL will be assessed at baseline and after cycle 1 and at the end of treatment using the PedsQL™ Cancer Module.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 10

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Princess Maxima Center For Pediatric Oncology

Sponsor organisation

Princess Maxima Center For Pediatric Oncology

Address

Heidelberglaan 25

City

Utrecht

Postcode

3584 CS

Country

Netherlands

Scientific contact point

Organisation

Princess Maxima Center For Pediatric Oncology

Contact name

Dr. F.J. Bautista

Public contact point

Organisation

Princess Maxima Center For Pediatric Oncology

Contact name

Dr. F.J. Bautista

Third parties 2

Locations

11 EU/EEA countries · 27 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 131 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

19 submissions — initial application plus substantial / non-substantial modifications